Diphosphoryl derivatives of thioethanolamine

ABSTRACT

Diphosphoryl derivatives of thioethanolamine of the formula:   WHEREIN A and B each represent an alkyl, alkoxy, haloalkoxy, alkoxyalkoxy, alkylthio, alkenyloxy, alkenylthio, aryl, aryloxy, furlalkoxy, amino or substituted amino group, D and E each represent an alkyl or aryl group, R is hydrogen, methyl or ethyl; and X and Y each represent oxygen or sulfur, which are useful as anticholinesterase compounds and as agricultural acaricides.

United States Patent [72] Inventors Jean Marie Cheymol Paris;

Pierre Eugene Chahrier de Lassauniere, Paris; Thuong Than Nguyen, Olivet, Loiret;

Philippe Robert Saulgnac, Paris, all of France [21] Appl. No. 681,005 [22] Filed Nov. 6, 1967 Nov. 30, 197] [45] Patented Centre National de La Recherche [73] Assignee Scientifique Paris, France [3 2] Priority Nov. 7, 1966 [3 3 France 3 I 83,766

[54] DIPHOSPHORYL DERIVATIVES 0F THIOE'IHANOLAMINE l2 Claims, No Drawings I52] U.S. CI 260/926, 260/247, 260/247.2 B, 260/293.4 B, 260/347.2,

[51] lnt.Cl A0ln9/36, C07f 9/08, C0 7f 9/24 [50] Field of Search 260/926, 959

[56] References Cited UNITED STATES PATENTS 3,] 17,150 l/l964 Kerschner et al 260/926 Primary ExaminerCharles B. Parker Assistant Examiner- Richard L. Raymond Attorney-Stevens, Davis, Miller & Mosher ABSTRACT: Diphosphoryl derivatives of thioethanolamine of the formula:

A B P-SCHz-NR15\ DO/JQ Y OE DIPHOSPHORYL DERIVATIVES OF THIOETHANOLAMINE The present invention provides, as new compounds, diphosphoryl derivatives of thioethanolamine of the formula:

- represent an alkyl or aryl group, R is hydrogen, methyl or ethyl and X and Y each represent oxygen or sulfur. Preferably A and B each represent lower alkoxy, chloro (lower alkoxy), lower alkoxy (lower alkoxy), lower alkenylthio, phenoxy, furfuryloxy, di(lower alkyl) amino, piperidino, or morpholino, and D and E each represent lower alkyl or phenyl. As used herein, the tenn lower as applied to an organic radical means that the radical in question contains not more than four carbon atoms. I

According to a feature of the invention the compounds of formula I are prepared by reacting together an N-(Bhalogenoethyl)phosphoramide or thiophosphoramide and'a salt of a thiophosphoric or dithiophosphoric acid of the respective formulas:

EOY

III

where Hal is halogen, preferably bromine, M is a cation preferably of an alkali metal such as sodium; or aitetraalkylammonium, e.g., tetramethyl-ammonium, ion and A B, D, E, R, 'X and Y are as hereinbefore defined.

The condensation of the phosphoramide or thiophosphoramide of formula II with the thiophosphate or the dithiophosphate of formula III may-be carried out in an inert organic diluent such as chloroform or acetonitrile.

The starting phosphoramide or thiophosphoramide of formula Il may be prepared by condensing a 2 halogenoethylamine with a halide, preferably chloride of a phosphoric or thiophosphoric acid of formula Hal-P represented as follows:

ll Y OE The bromides of formula Y OE are new compounds and form part; of the invention.

The following nonlimiting examples'illustrate the invention.

EXAMPLE I a. 0,0-diisopropyl-N B-bromoethylphosphoramide.

Into a 250 ml. threenecked round-bottomed flask provided with a dropping funnel, a stirrer, a thermometer and asilica gel tube to isolate it from the outside, 0.! mol. of diisopropyl chlorophosphate in solution in 100 ml. of anhydrous chloroform is introduced. 0.l mol of dry, finely crushed bromoethylamine hydrobromide is added. A solution of 0.22 mol of triethylamine (10 percent excess) in 25 of anhydrous chloroform is slowly added drop-by-drop at between 25 and 30 C. The solution obtained when the addition has been completed is completely clear and slightly colored. The stirring is continued for l hour after the addition.

The product is washed two to three times with distilled water and thechloroform solution is collected and dried over sodium sulfate.

The chloroform is driven ofi in vacuo and the product is distilled, under a low pressure of nitrogen maintainedby a pump, to obtain the pure product. Regardless of the precautions taken the distillation is always accompanied by slight decomposition. At the end of the distillation, the phosphoramide crystallises, b.p. l00l03 C./ 0.05 mm. Hg, 70 percent yield.

Analysis:

Calculated percent:C=33.3, H%.5, N=4.86, P=l0.74,

Found percent:=C 33.46, H=6.62, N=4.93, P=l0.85,

b. 0,0-dimethyl-S-(0,0-diisopropylphosphoramido) ethyl thiophosphate.

0.1 mol of diisopropyl-B-bromoethylphosphoramide in solution in 60 ml. of anhydrous chloroform is introduced into a flask. To this solution 0. I05 mol of tetramethylammonium O, O-dimethylthiophosphate is rapidly added. The flask is hermetically sealed and heated to 40 C. on the water bath. A white precipitate of tetramethylammonium bromide appears after a few moments. The heating is continued for several hours to complete the reaction.

After cooling, the tetramethylammonium bromide is collected percent yield). The filtrate is washed with a 4 percent aqueous sodium bicarbonate solution until an alkaline pH is obtained, and then 2 to 3 times with distilled water. The product is dried over sodium sulfate and the chloroform is completely driven off in vacuo at 40 C. 27 g. of a very slightly colored oil, n "=1 .4654, 79 percent yield, are obtained.

EXAMPLES 2 to l6 a. By the procedure of example la employing other acid chlorides, the following compounds are obtained:

Y' 1d, Formula Acid chloride B.P. CJmm. Hg or M.P. C. per c ent ((lllzOhPNllCIizCllzBr (CH30)1PCl B.P./0.05 mm.Hg=118-119. Only 66 II 307 of the compound disitils. It decomposes spontaneously at about 175 C.

(CzHgOhIfiNHCHzCHzBf (CzHrOhfiCl Decomposes at about 170 (3..-. 1 76 0 0 (n-C:H)zI|E|NHCHCH:Br (n-C;H1O):lICl B.P./0.06 mm.Hg=123-124 C 69 cmlonfi'NncmcHmr (CoHsOhfiCl M.P.=45 C 80 (ClC2H O)zIllINHCHzCH:Br (C1C2 10)2:fi01 About C 80 (C2H 0)1PNHCH:CH2B! (C2H5O):PC1 Undistillable liquid l 87 (n-CaH70)zPNHCH:CHzBr (H-CaH'rOhP Cl d0 1 89 M.P.=7172 C. 55 O N-PNHCHaCHzBr O NP Cl J/|| 0 0 061150 Cal-I50 l Yields 0! crude product. I v V Y b. From the bromoethylphosphoramides of part a of examsalts specified in the following table, the compounds identified pie 1 and of the present examples and from the ammonium 30 in the first column of the table are prepared:

Relractlve Example index flu or Yield, No. Formula melting point percent 54 .l ClhO 1.407 m /fi-SCH:CH;NH-fi (-1C,n1), ClIaOClhCHaO O O /{|SClIzClI:N-P (OCdh); ClIrOCIhClhO O 7 CH:

56 c1110 7 l. 4765 an /f|SClhClhN--l] (0lC,u,), ClhOCIIzClhO 0 n,

57 cmo 1. 4520 x15 lSCll;Cll;N-l[ (O-lCalh): cu cmo 0 in, 0

a 1. um in Clt\ P-SCll1ClhNll-l (00,15), 0 u u C1110 0 0 69 e 4 CHxO PSClI1CH:NHi;(OC|Ht)1 L606 78 cm=cncms 60. CIiaO P-SClhClbNlF-fi (O-lCaH1)| 1. 4900 M CH|=CHCH|S bl C1110 I-SCHICH1NP(O 0:115): 1.4761 84 CH1=CH CHIS I1:

02 ClhO P-SCHrCIhN f(O-lC|il1)r 1.469 01 Clh=Cll0lhS lh P-SCHgCHIN-P(O-lCxIfi): 1.1680 90 CII|=CH GU18 an:

None of these compounds could be distilled. The elementa- 4o 1s ry analyses gave satisfactory results. The new compounds of formula I are fairlymobile, slightly u "0 colored oils which are soluble in the usual organic aolvents,5 u an lparingly soluble in water and only slightly odiferoua. 0 They have low toxicity. as shown in the following table. 90

Product of Example LD 50 (moule; lntraperltoneal; I

N In A l Some are endowed with intense anticholineateraae activity comparable to that of neoetigmine, so that they may be employed in therapeutic: using this activity e.g.. in their myotic 1 action, indirect paraaympathomimetic action. or action on the n 500 to 625 60 IICUIOMUSCUiBfjUIlCUOD).

i: The following table gives the toxicity and anticholinesterase 2o 6 activity of two of the new compounds. 24 412 25 ll 26 100 Antleholln- 17 s :0 IO M) 60 (mouse; oetenue no u 5 lntraperttotlvlty ID N "nu-"noun Compound noel; rum/kg.) y/ml. a-olmo Pimomcm s P o cum. as Between 04 ll and 0.8. :2

a g: m wimom'xmomoma mouth)..." 00 Do. as in S6 66 37 Nooatlgmlne 0.17. n n I 75 1 lD -lnhlbltlng dose.

Examination of the NMR spectra of the two compounds 4. Acompound according to claim 1 of the formula: shows that they contain about 10-15 percent of their isomers O CH: 5 (R01) P-NH-CHr-CHzO-P 5 ll II CH3 5. A compound according to claim 2 of the formula:

7 (lower alkoxy)1fiS CHICH2NH P-(phenoxy): formed by isomerisation of the tetramethylammonium salt 10 V s 0 v 6. A compound according to claim 2, wherein E is lower alkyl and A is lower alkyl or lower alkoxy. (CHa0),P\ N(OH;)4 7. A compound according to claim 4 of the formula:

7 W (lower alkoxyhlfi- S CHzCI-IzNH fi-(chloroethoxyh during their preparation. r S r O The compounds of formula I are also useful as acaricides and may be used for this purpose'in agriculture.

The invention therefore includes within its scope pharmaceutical and agricultural compositions comprising one or (methoxy)2 P SCHaCHINH#fi mopmpyloxy) more of the compounds of formula I in association with an in- Na ,9 A: v, O ert, compatible pharmaceutical or agricultural carrier. Such compositions may be made up using diluents and methods 8. The compound according to claim 6 of the formula:

9. The compound according to claim 6 of the formula:

k th t' rts.

az g f Spec We a (methoxyh-fi-S OHzCHzNH-fi (ethoxy):

l. A diphosphoryl derivative of thioethanolamine of the for- O O mula: v A V. a: 7.: H a a a .7

A B 10. The compound according to claim 6 of the formula:

P-S oH,oH,NB fi 3O methyl D 0 Y 0E PS cmomNn-fi (iao-propyloxy): wherein each of A and B is lower alkoxy, halo (lower alkoxy), lmlti lffi'v at O I lower alkoxy (lower alkoxy), lower alkenylthio, phenoxy or di (lower alkyl) -amino; 11. The compound according to claim 6 of the formula:

D is lower alkyl or phenyl; E is lower alkyl, chloroethyl or phenyl; methoxy R is hydrogen, F y ethyl; and P-s omomNH-m (ethoxyh each of X and Y 15 oxygen or sulfur. I ll 2. A diphosphoryl derivative according to claim 1 in which 40 l fif 0 A and B each represent lower alkoxy, chloro(lower alkoxy), i lower alk xy lk xy). lower alkenylthiot ph n y, di 12 The compound according to claim 6 of the formula: (lower alkyl) amino, and D and E each represent lower alkyl or phenyl. methoxy 3. A compound according to claim 2 of the formula: P-S CHflCHtNH-fi (ethoxy);

(lower alkoxy)all S CHzCHrNH fi-(lower alkoxy): "-D p y 0 v HY. I V v .v V I 

3. A compound according to claim 2 of the formula:
 4. A compound according to claim 1 of the formula:
 5. A compound according to claim 2 of the formula:
 6. A compound according to claim 2, wherein E is lower alkyl and A is lower alkyl or lower alkoxy.
 7. A compound according to claim 4 of the formula:
 8. The compound according to claim 6 of the formula:
 9. The compound according to claim 6 of the formula:
 10. The compound according to claim 6 of the formula:
 11. The compound according to claim 6 of the formula: 12 The compound according to claim 6 of the formula: 